Interferon-alpha (IFN alpha) concentrations are increased in conditions associated with tissue injury. To investigate the endocrine and metabolic actions of IFN alpha in vivo, we studied eight healthy controls on two occasions, once after administration of 5 million units/m2 rhIFN alpha and once after administration of saline (control). Rates of appearance (Ra) of glucose and glycerol in plasma were measured by infusion of [3-3H]glucose and D5-glycerol, respectively. Energy expenditure and substrate oxidation were determined by indirect calorimetry. IFN alpha induced increases in plasma concentrations of norepinephrine (225 +/- 93%; P < 0.02 vs. control), epinephrine (272 +/- 80%; P < 0.05), cortisol (353 +/- 63%; P < 0.02), glucagon (50 +/- 12%; P < 0.05), free fatty acids (223 +/- 61%; P < 0.02), and glycerol (68 +/- 21%; P < 0.02) and in resting energy expenditure (36 +/- 50%; P < 0.03). The Ra of glycerol (169 +/- 39%; P < 0.02) and fat oxidation (104 +/- 23%, P < 0.02) were also increased after IFN alpha treatment. The Ra of glucose was higher at the end of the recombinant human IFN alpha treatment day than in the control experiment (12.83 +/- 1.08 vs. 9.34 +/- 0.46 mumol/kg.min; P < 0.03). It is concluded that IFN alpha administration induces, directly or indirectly, major endocrine and metabolic changes and is probably part of the cytokine network mediating the endocrine and catabolic reactions to tissue injury.